The fact that vitamin D plays a vital role in formation of bones as it regulates absorption of calcium and reabsorption of bone inorganic substances by intestine has recently been made known by an extensive research on metabolites of bone (H. F. DeLuca et al., Ann. Rev. Biochem., vol. 52. p. 411, 1983).
It has also been known that some vitamin D.sub.3 derivatives have the function of inducing cell differentiation, suggesting enormous potential applications of vitamin D in the future (T. Suda et al., Bone & Mineral Res./4. ed. W. A. Peck, Elsevier, Amsterdam, p. 1, 1986).
1.alpha.,25-dihydroxty vitamin D.sub.3 (N. Ikegawa et al., Organic Synthetic Chemistry, vol. 37, p. 755, 1979) and 1.alpha.-hydroxy vitamin D.sub.3 (C. Kaneko, Organic Synthetic Chemistry, vol. 33, p 75, 1975) which are chemically analogous to each other and actively substantiate the above described effects have been attracting attention and are currently used as medicines for diseases such as chronic nephric insufficiency, while the latter has proved to be an excellent medicine for curing osteoporosis.
Under these circumstances, researches have been actively conducted on synthetic preparation of derivatives of 1.alpha.-hydroxy vitamin D.sub.3 which are regarded as indispensable for substantiating biogenic activities (B. Lythgoe, Chem. Soc. Rev., vol. 9, p. 449, 1980; R, Pardo et al., Bull. De La Soc. Chim. De Fr. p. 98, 1985).
Currently, the process of synthesis of derivatives of 1.alpha.-hydroxy vitamin D.sub.3 typically starts with synthesis of 1.alpha.-hydroxylated steroid, which is converted to corresponding 1.alpha.-hydroxy-5,7 dienesterol and then to the intended vitamin D derivative by using known photochemical techniques. However, this known process comprises a number of steps, making the overall processes rather inefficient. (See above-cited C. Kaneko's paper.)
With a view to overcome these problems, a number of improved processes have recently been proposed, which can be categorized into the following three groups or groups (a), (b) and (c).
Group (a).
1) direct hydroxidation of vitamin D.sub.3 and related compounds at C(1); H. F. De Luca et al., J. Org. Chem., vol. 45, p. 3253, 1980 PA0 2) preparation of 1.alpha.-hydroxylated compounds; H. F. De Luca et at., Japanese Patent Application No. 54-555366 PA0 3) derivatives of cyclovitamin D; H. F. De Luca et al., Japanese Patent Application No. 57-206229 PA0 4) derivatives of 1.alpha.-hydroxycyclo vitamin D; H. F. De Luca et at., Japanese Patent Application No. 57-206230 PA0 5) derivatives of 1-oxocyclo vitamin D; H. F. De Luca et al., Japanese Patent Application No. 57-206231 PA0 1) direct-positional or stereoselective .alpha.-hydroxylation of a (5E)-calciferol derivative; R. H. Hesse et al., J. Org. Chem., vol.51, p. 1635, 1986 PA0 2) synthesis of 25-hydroxy vitamin D.sub.3 and 1.alpha., 25-dihydroxy vitamin D.sub.3 from vitamin D.sub.2 ; R. H. Hesse et al., J. Org. Chem., vol. 51, p. 4819, 1986 PA0 3) synthesis of MO-903, a metabolite of biogenetic vitamin D; M. J. Calverley, Tetrahedron, vol. 43, p. 4609, 1987 PA0 1) Synthesis of A-ring of 1S-hydroxykohlcalciferol; D. Desmaele et al., Tetrahedron Letters, vol. 16, p. 4941, 1985 PA0 2) Improved synthesis of an A-ring of 1.alpha.,25-dihydroxy vitamin D; L. Castedo et al., Tetrahedron Letters, vol 28, p. 2099, 1987 PA0 3) Stereoselective synthesis of Lynthgoe A-ring aldehyde for synthesis of 1.alpha.-hydroxytachysterol and calciferol; E. G. Baggiolini et al., Tetrahedron Letters, vol. 28, p. 2095, 1987 PA0 4) simplified synthesis of Enyne A-ring of 1.alpha.-hydroxy vitamin D; W. H. Okamura et al., Tetrahedron Letters, vol. 28, p. 4947, 1987 PA0 5) stereoselective synthesis of 1.alpha.,25-dihydroxykohlcalciferol and 1.alpha.,25-dihydroxyergocalciferol; E. G. Baggiolini et al., J. Org. Chem. vol. 51, p. 3098, 1986 PA0 6) ergocalciferol derivatives; E. G. Baggiolini et al., Japanese Patent Application No. 59-52417 PA0 7) calcifenol derivatives; E. G. Baggiolini et al., Japanese Patent Application No. 60-22091 PA0 R.sub.1, R.sub.2, R.sub.3 and R.sub.4 represent not necessarily identically a hydrogen atom or a hydroxy protecting group; and PA0 X represents a hydrogen atom, a hydroxy group or its derivative.) PA0 R.sub.1, R.sub.2, R.sub.3 and R.sub.4 represent not necessarily identically a hydrogen atom or a hydroxy protecting group; and PA0 X represents a hydrogen atom, a hydroxy group or its derivative.) PA0 R.sub.1, R.sub.2 and R.sub.3 represent not necessarily identically a hydrogen atom or a hydroxy protecting group; and PA0 X represents a hydrogen atom, a hydroxy group or its derivative.)
In any of the group (a) processes, a vitamin D derivative is converted to a derivative of 3,5-cyclovitamin D, which is then combined with an allylic acid at positon C(1), said compound being further converted to a derivative of vitamin D.
Group (b)
Any of the group (b) research papers proposes a process where vitamin D is temporarily combined with allylic acid at position C(1) to convert it to transvitamin D, which is then reconverted to vitamin.
Group (c)
Group (c) represents efforts to attain a totally synthetic process in which a chemical fragment that corresponds to an A-ring having a hydroxyl group at C(1) position is synthesized, to which fragments that correspond to a C-ring and a D-ring are combined to obtain the aimed compounds. However, such a process consists of a number of steps and hence does not provide a simple, economic and satisfactory method of manufacturing the compounds in practical applications. Moreover, compounds which are obtained by such a process do not necessarily exhibit satisfactory chemical effects.
It is therefore an object (the first object) of the present invention to provide novel and chemically useful 1.beta.,7,8-trihydroxy vitamin D.sub.2, 1.beta.,7,8-trihydroxy vitamin D.sub.3 and their derivatives.
It is another object (the second object) of the present invention to provide an industrially efficient and effective method of manufacturing above chemicals by directly combining vitamin D.sub.2, vitamin D.sub.3 or any of their derivatives with an oxygen function group at position C(1) through utilization of chemical reaction of allylic acid as described later, a method which is completely different from any exisiting synthetic methods in terms of basic concept and practical applications.